, 2009). Given recent evidence that radially aligned cells arising from a common progenitor have a high probability of interconnecting ( Yu et al., 2009), the tangential dispersion at the multipolar cell phase may also be critical for establishing intercolumnar cortical connectivity ( Costa and Hedin-Pereira, 2010). Our work adds

to these findings by demonstrating that the timing and Selleckchem Decitabine duration of the multipolar phase is precisely regulated by FoxG1 activity. Pulse-chase studies have shown that cell birth date within the cortex predicts laminar position (Angevine and Sidman, 1961 and Rakic, 1974). A now classic transplantation study found that cell fate could be altered depending on whether pyramidal neurons underwent their last neuronal division in an isochronic or heterochronic host environment (McConnell and Kaznowski, 1991). Our study adds to this finding by demonstrating that the laminar position and postnatal marker expression of pyramidal neurons remains labile at least up to the early multipolar phase. In this regard, both the laminar (Kwan et al., 2008 and Lai et al., 2008) and

areal (Joshi et al., 2008) identity of pyramidal neurons require the persistent expression of the transcription factors (Sox5 and BhlhB5), which are exclusively restricted to postmitotic cells. It will take further analysis to establish whether the mispositioning of pyramidal neurons upon FoxG1 gain-of-function results in changes in their hodological identity. Nonetheless, it is becoming evident that rather than being irreversibly fixed, pyramidal neurons require active maintenance in their identity, Volasertib demonstrating that the line between developmental programs and adult plasticity is less absolute than previously recognized. In addition to its roles in axon outgrowth and growth cone turning in commissural projection neurons (Serafini et al., 1994), Netrin-signaling has been shown to mediate both attraction and repulsion during cell migration (Ackerman et al., 1997, Alcántara et al., 2000, Hu and Rutishauser, 1996, Stanco et al., 2009 and Xu et al.,

2010). Oxymatrine It has also been suggested that Netrin-signaling controls axon outgrowth and cell migration through distinct downstream mechanisms (Causeret et al., 2004). Here, we show that, in the case of pyramidal neuron precursor migration, Unc5D and Dcc function in concert during the multipolar cell phase. In this context, FoxG1 appears to regulate the expression of Unc5D but not Dcc. Interestingly, in Drosophila motorneurons akin to the present context, Unc5 is positively regulated by the transcription factor Even-skipped, whereas Frazzled (the fly homolog of Dcc) is not ( Labrador et al., 2005). Netrins and, more recently, Flrts (Fibronectin type III domain and leucine-rich repeats transmembrane protein) have been demonstrated to interact with Unc5 receptors (Karaulanov et al., 2009 and Yamagishi et al., 2011).

g., Ray and Maunsell, 2010, Siegel and König, 2003 and Vinck et al., 2010), and can also be modulated by cognitive functions, such as attention (Fries et al., 2001) and memory (Pesaran et al., 2002). It remains to be investigated whether extracellular findings on synchronization could be accounted for by Vm synchrony among a large population

of local neurons. An intriguing possibility is that Vm synchrony not only exists but is even more versatile in the awake brain and is fundamental to many cognitive functions, including perception. Anesthesia was induced in adult female cats aged 4–6 months with ketamine hydrochloride (30 mg/kg i.m.) and acepromazine maleate (0.3 mg/kg i.m.), and was maintained by intravenous infusion of sodium thiopental (20 mg/kg initial; 1–2 mg/kg/hr selleck screening library maintenance) or a mixture of propofol and sufentanil (5–10 mg/kg/hr + 0.75–1.5 μg/kg/hr, i.v.). After initial surgery, paralytic

(vecuronium bromide, 1.5 mg/kg initial dose, 0.2 mg/kg/hr maintaining rate) was administered and the animal was artificially ventilated through a tracheal cannula (end-tidal CO2: 3.6%–4.0%). To improve recording stability, the thoracic vertebrae were suspended and a bilateral pneumothoracotomy was performed. Body temperature was feedback controlled with a heating lamp at 38°C. Depth of the anesthesia was assessed by EEG pattern and heart rate stability. All vital parameters PI3K Inhibitor Library solubility dmso (heart rate, EEG, CO2 ratio, and temperature) were continuously monitored and recorded. All procedures were approved by the Northwestern University Animal Care and Use Committee. The pupils were dilated with 1% atropine and the nictitating membranes retracted with 2.5% isothipendyl phenylephrine hydrochloride. Contact lenses were inserted and corrective lenses were placed to focus the retina on a computer monitor (ViewSonic, Walnut, CA) 50 cm distant from the eyes. Sinusoid drifting gratings were generated on the monitor using the Psychophysics toolbox (Brainard, 1997 and Pelli, 1997) running under Matlab (MathWorks, Natick, MA).

The monitor refresh rate and mean luminance were 100 Hz and 20 cd/m2. Gratings were usually less than 4 degrees in radius and were large enough to cover the receptive fields of both cells in a recorded pair. Stimuli were presented monocularly, although binocular stimulation did not change the basic findings on Vm synchrony. For studying orientation dependence of synchrony, the stimulus spatial frequency was chosen to lie between the optimal spatial frequencies of two cells in a pair. In each trial, a blank period (0.25–1 s) preceded and followed visual stimulation (1.5–4 s). One or two blocks of blank stimulation were presented for each set of stimuli. Stimuli in a set were presented in random order and the set was repetitively presented for 5–20 times.

These experiments help define limits on the role of intrinsic factors in cortical development and establish a role for extrinsic, presumably activity-dependent factors on cortical columnar, laminar, and neuronal morphological development. To examine the role of thalamocortical neurotransmission in cortical development, we generated mice in which glutamatergic release is disrupted in thalamocortical Cytoskeletal Signaling inhibitor neurons using a Cre/loxP recombination approach. We focused on vesicular glutamate transporters, of which there are three known

genetic forms in mice (Vglut1–3). Vglut3 is expressed weakly and sporadically in the brain, while Vglut2 and Vglut1 have strong and largely complementary expression patterns ( Fremeau et al., 2004), with Vglut2

robustly expressed in the thalamus and Vglut1 to a lesser extent. Because Vglut2 null mice die at www.selleckchem.com/products/AZD6244.html birth ( Moechars et al., 2006), we crossed floxed Vglut2 mice (Vglut2fl/fl; Hnasko et al., 2010) with the Sert-Cre driver line ( Zhuang et al., 2005) to delete Vglut2 from thalamocortical projection neurons. Somewhat to our surprise, thalamocortical neurotransmission in these mice was indistinguishable from that in control mice ( Figures 1A–1E). Reasoning that Vglut1 may compensate for the absence of Vglut2 in thalamic neurons, we generated mice that lacked Vglut1 and Vglut2 in the thalamus by crossing Sert-Cre mice with Vglut1+/−;Vglut2fl/fl mice to generate Vglut1 and Vglut2 double knockout mice (Sert-Cre+/−;Vglut1−/−;Vglut2fl/fl, or ThVGdKO). ThVGdKO mice had severely disrupted thalamocortical neurotransmission, whereas all littermate control mice, even those with just a single copy of Vglut1 or Vglut2, had thalamocortical neurotransmission that was grossly indistinguishable from that in wild-type (WT) mice ( Figure 1). almost We measured the effect

of Vglut deletion on thalamocortical neurotransmission in two ways. First, we used in vitro electrophysiological techniques to examine miniature excitatory postsynaptic current (mini-EPSC) amplitude and frequency in thalamocortical brain slices ( Crair and Malenka, 1995) across a range of ages (postnatal days 4–15, P4–P15). Mini-EPSCs were measured using whole-cell patch-clamp recordings from layer 4 (L4) neurons following thalamic stimulation after replacing Ca2+ with Sr2+ in the extracellular medium to desynchronize neurotransmitter release ( Iwasato et al., 2008). In 5 of 11 ThVGdKO mice at P9–P11, we could not evoke a measurable thalamocortical response. In the remaining six ThVGdKO mice at P9–P11 ( Figures 1C–1E), evoked mini-EPSC amplitude (3.9 ± 0.18 pA) and frequency (0.28 ± 0.24 Hz) were much smaller in comparison to littermate controls (p < 0.01). Neither single knockout of Vglut1 (Vglut1−/−;Vglut2fl/−; amplitude: 8.44 ± 1.78 pA; frequency: 8.0 ± 1.18 Hz; n = 6) nor thalamic deletion of Vglut2 (Sert-Cre+/−;Vglut1+/−;Vglut2fl/fl, amplitude: 12.92 ± 0.

, 2007 and Mutch et al., 2009). Cells electroporated with constitutively active β-catenin as late as E15.5 generated neurons that occupied

deeper positions and expressed early subtype markers, and cells expressing dominant-negative β-catenin at E13.5 produced neurons showing the opposite effects (Mutch et al., 2009). Although these experiments Target Selective Inhibitor Library price are difficult to interpret given the multifaceted roles of β-catenin in RG biology, they suggest that the precise regulation of β-catenin signaling activity might be one approach for regulating excitatory neuron subtype production. Early cortical precursor cells transplanted into later stage cortex can adapt to the host environment and switch to production of upper-layer neurons (McConnell, 1988 and McConnell and Kaznowski, 1991). However, late cortical precursors transplanted into earlier stage cortex do not regain their competence to produce early-stage neurons (Frantz and McConnell, 1996), indicating that cell-intrinsic changes in competence make the neurogenic plasticity unidirectional— the “progressive restriction” model. In terms of decreasing β-catenin

activity (see above), these observations could be interpreted to suggest that, as neurogenesis

proceeds, the environmental signals that stimulate β-catenin signaling decline. At the same time, the progenitor cells HCS assay also become less competent to respond to higher signal levels, placing a ceiling on their potential range of β-catenin activity, and such a ceiling progressively lowers until neurogenesis is extinguished. Besides forced expression of constitutively active β-catenin, another molecular perturbation that can reset or “rewind” the progenitor cell’s neurogenic competence involves a temporary reduction in Foxg1 expression (Shen et al., 2006). Until we have a better understanding of the transcriptional and signaling circuitries that determine the output of those RG cell divisions, we will have to use alternative approaches to achieve single neuron subtype production. The timed application of the Notch pathway inhibitor DAPT has been used to force the differentiation of all progenitor cells at a given time (Eiraku et al., 2008). This is an effective means to obtain a pure population of layer I neurons or a mixed population of layer I and layer VI neurons, or of layers I, VI, and V, etc., depending on the timing of DAPT application. Eiraku et al.

We first screened for effective shRNAs that suppress each mRNA by at least 75% as measured by quantitative RT-PCR of mRNA levels and immunoblotting.

We then generated a lentivirus capable of expressing all four effective shRNAs from pol III promoters (the human H1 and U6 promoters) and a rescue construct from a pol II promoter (the ubiquitin promoter; Figure 1B). Expression of the four shRNAs against Doc2 family proteins yielded good suppression of all targets except for Doc2A, although the KD efficiency was not as high as with lentiviruses expressing only a single shRNA. Thus, to maximize the Doc2A KD, we generated a second lentivirus Enzalutamide expressing another Doc2A shRNA (Figure 1B) and superinfected the cultured cortical neurons with both viruses. This procedure produced ∼75% KD of all four targets, allowing us to analyze the effects of such a loss-of-function manipulation (Figures 1C and 1D). Because Doc2B is a proposed Ca2+ sensor for spontaneous release (Groffen et al., 2010), we first tested the effect of the quadruple KD of Doc2A, Doc2B, Doc2C, and rabphilin (Doc2/rabphilin KD, or DR KD) on spontaneous miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs, respectively). Consistent with observations in Doc2A/Doc2B double KO mice (Groffen et al., 2010),

we found that the DR KD reduced spontaneous inhibitory and excitatory minirelease by >60% (Figures 1E–1H) ERK inhibitor without altering neuronal cell density or synapse numbers

and sizes (Figure S1A, available online). With any shRNA-mediated KD, off-target effects are a major concern (Alvarez et al., 2006) even if the KD reproduces the KO phenotype (Groffen et al., 2010). To exclude off-target effects, we performed why rescue experiments by coexpression of shRNA-resistant Doc2A or Doc2B alongside the shRNAs. Surprisingly, we found that Doc2A expression rescued the impairment of spontaneous minirelease in excitatory but not inhibitory synapses in DR KD neurons, whereas Doc2B conversely rescued the mIPSC but not the mEPSC phenotype (Figures 1E–1H). To determine whether the DR KD acts postsynaptically, we transfected the lentiviral vectors resulting in the expression of the DR shRNAs and EGFP in only a few neurons. Electrophysiological recordings from transfected, fluorescent neurons detected no changes in mIPSC frequency (Figure S1C), suggesting a presynaptic role for Doc2 proteins. Most spontaneous release is suppressed by BAPTA-AM, suggesting it is largely Ca2+ dependent (Li et al., 2009 and Xu et al., 2009). To test whether the DR KD changes the Ca2+ dependence of spontaneous release, we titrated the extracellular Ca2+ dependence of the minifrequency.

, 2011 and Momin et al., 2008). Selleckchem SB431542 The evidence for changes in HCN protein and transcript levels after nerve injury are somewhat contradictory and may be explained by somatic versus axonal compartmentalization ( Chaplan et al., 2003 and Jiang et al., 2008). However, even if expression changes are minimal, alterations in cAMP levels could contribute to modified Ih densities, and it is conceivable that inhibitors that block adenyl cyclase exert some of their analgesic action in neuropathic pain models

in the periphery by reducing HCN channel sensitization ( Wang et al., 2011). How does Ih contribute to generating ectopic discharges? Because of activation by hyperpolarizing potentials, HCN channels

are also an important component for membrane FRAX597 potential oscillations in various neuronal networks ( Biel et al., 2009). Especially in concert with low-threshold T-type calcium channels, neurons can display repetitive firing patterns, where hyperpolarization leads to activation of Ih, slowly depolarizing the membrane potential until a Ca2+ spike carried by T-type calcium channels is initiated, further depolarizing the potential and triggering a series of Na2+ spikes. The depolarization inactivates Ih until the train of action potentials is followed by a hyperpolarizing overshoot, which opens HCN channels and the cycle can repeat ( Biel et al., 2009). This model also explains the observed analgesic effect of peripherally applied T-type antagonists in neuropathic pain models ( Barton et al.,

2005 and Dogrul et al., 2003). Given their contribution to generator potentials in the peripheral terminal and action potentials in the axon, it is not surprising that voltage-gated sodium channels (VGSC) have been a prime target of investigation and therapeutic approaches for neuropathic pain (Devor, 2006 and Dib-Hajj et al., 2010). Nav1.8 is mainly expressed by A- and C-fiber nociceptors, Nav1.9 is selective for a subset of C-fibers, whereas Nav1.1 and Nav1.6 are found mostly in nonnociceptive neurons (Fukuoka et al., 2008 and Fukuoka and Noguchi, 2011). Nav1.7 seems to be Etomidate expressed universally in all sensory neurons, but clearly plays an important role in nociception, as indicated by various monogenetic disorders affecting this channel, including gain of function mutations in Nav1.7 that result in ectopic firing of C-fibers in the absence of nerve injury and spontaneous pain conditions (Cox et al., 2006, Dib-Hajj et al., 2010 and Faber et al., 2011). Nav1.3 is usually only expressed during development (Waxman et al., 1994); however, nerve injury drastically changes this expression profile and expression of Nav1.3 returns in adult sensory neurons (Fukuoka et al., 2008 and Waxman et al., 1994). Notably, Nav1.

Thus, the intracellular trafficking and synaptic targeting of NMDA receptors should be one of the prerequisites for NMDA receptor activity ( Lau and Zukin, 2007 and O’Brien et al., 1998). However, little is known about the precise roles and mechanisms of NMDA receptor transport in vivo. In the present study, we determined that KIF17 is critical to maintain NR2A/2B levels in different manners and that it Selleckchem MK2206 is required for multiple processes of long-term memory formation in the mammalian brain. Furthermore, we found that NR2B receptor supply is augmented on demand through a reciprocal interaction between CREB and NR2B/KIF17. Thus, our data

suggest that KIF17 is critical for a complex regulatory mechanism involving cargo transport, nuclear transcriptional signaling, and protein degradation that controls the levels of NR2A/2B.

We generated mice with a disrupted kif17 gene using a poly(A) trap strategy (see Figures S1A–S1C available online). Absence of KIF17 in kif17−/− mouse brain was verified by immunoblotting with a polyclonal antibody against KIF17 ( Figure S1D). The kif17−/− mice grew normally without any gross anatomical defects in brain ( Figures S1E–S1G). Immunoprecipitation demonstrated selleckchem that KIF17 interacts with NR2B but not with NR2A in hippocampal extracts (Figure 1A; Setou et al., 2000). The level of NR2B protein in the hippocampi of kif17−/− mice was decreased to 42% of that in kif17+/+ mice ( Figure 1B). There was also a reduction ADP ribosylation factor in the levels of NR2A and Mint1 (a scaffolding protein that binds to KIF17 to mediate NR2B transport; Setou et al., 2000), but no change in the levels of other related proteins ( Figures 1B and S2A).

The levels of nr2b mRNA in the hippocampi of kif17−/− mice were decreased compared with those in control mice, but the levels of nr2a mRNA were not ( Figure 1C). An RNA stability assay, using cultured hippocampal neurons treated with actinomycin D (10 μg/ml, an inhibitor of mRNA transcription), revealed no difference in the half-lives of both NR2B mRNA and NR2A mRNA between kif17+/+ and kif17−/− neurons ( Figures 1D–1F). Immunoreactivities for NR2B and NR2A in the hippocampal CA1 region of kif17−/− mice were reduced compared with those in control mice ( Figure S2B, upper panel and middle panel). Biochemically, kif17 deletion reduced the levels of NR2B and NR2A in synaptosomal membrane fractions by 43% and 22%, respectively, compared with those in kif17+/+ mice ( Figures 1G, S2C, and S2D). These data indicate that the amounts of synaptic NR2B and NR2A are decreased in kif17−/− mouse hippocampal neurons. To study NR2B/2A localization in kif17+/+ and kif17−/− mouse neurons in detail, we performed immunocytochemistry using hippocampal cultures. The lack of KIF17 resulted not only in a decreased density of NR2B/2A-positive clusters along dendrites, but also in a reduced size of NR2B/2A clusters in neurons ( Figures 2A–2F).

, 2007),

but a similar question has not been explored in early sensory systems. Furthermore, previous theoretical work has suggested that an optimal model that updated its prior probability is inconsistent with observed physiological data, precisely because such a model would not predict adaptation (“repulsion” of a tuning curve), but an opposite effect (“attraction”) (Stocker and Simoncelli, 2006). In fact, in the primate lateral geniculate nucleus selleck and primary visual cortex, stimulus-specific enhancement of sensitivity from peripheral stimuli has been explained by a model containing adaptation of an inhibitory surround pathway analogous to what we have proposed (Camp et al., 2009 and Wissig and Kohn, 2012). As to whether this behavior might be consistent with updating of a prior stimulus probability, it has been noted that, during low-contrast or noisy stimuli, prior information would become particularly important, but these conditions have not been thoroughly explored (Schwartz et al., 2007)—most likely because conditions of strong stimuli are often more amenable to experimentation. In fact, we observed sensitization under conditions of weak stimuli, when prior information from nearby or previous strong stimuli is most critical in detecting signals in a noisy

environment. Several lines of evidence suggest that sensitization first arises in the bipolar cell presynaptic terminal, although a definitive confirmation must come from more mechanistic U0126 future experiments. Sensitization produces a horizontal shift on the ganglion cell nonlinearity (Kastner and Baccus, 2011). For such a shift to occur, a steady change in inhibition must be delivered prior to a strong threshold, as occurs at the bipolar cell terminal (Heidelberger and Matthews, 1992). Furthermore, although GABAergic transmission is required for sensitization (Figure 8), transmission

through GABAA receptors is not. Thus, GABAergic transmission directly on to ganglion cells is not required whatever for sensitization (Figure 8), indicating a requirement for transmission through GABAC receptors on bipolar cell terminals. Finally, recordings from a subset of bipolar cells show a depolarization after high contrast. These bipolar cells connect to fast Off cells (Figure 9). Consistent with this proposal, a recent study shows that an increased transmission from bipolar cells in zebrafish requires GABAergic transmission, and depression of amacrine transmission to bipolar cell terminals may underlie sensitization in ganglion cells (Nikolaev et al., 2013). The depolarization observed in bipolar cells could underlie the shift in threshold and, potentially, the decrease in slope seen during sensitization.

72 × σMN were set to 0 (3.72 is the approximate Z score value of p = 0.9999, i.e., only 1 in 10,000 values click here will be above this threshold by chance). The median σMN value was 0.078, and 95% of σMN values were below 0.2. Cells were considered active if they crossed the 3.72 × σMN threshold for at least 500 ms

(nine frames). Cells were considered predominantly activated by a stimulus condition if average response during one condition was at least twice as high as average response during any of the other conditions. We thank Tara Keck and Tony Movshon for comments on the manuscript. This work was supported by the Max Planck Society and fellowships from the Swiss National Science Foundation and the Human Frontier Science Ku-0059436 mw Program to G.B.K. “
“Despite the widespread belief that neural

circuit formation is the central theme of vertebrate neural development, there is ample evidence of the opposite: postsynaptic target cells in various parts of the central and peripheral nervous system appear to be innervated by more axons early in postnatal life than later on (Purves and Lichtman, 1980). The reduction in the number of converging axons, known as synapse elimination, may play a role in establishing permanent synaptic circuits based on experience (Lichtman and Colman, 2000). In the neuromuscular system, this phenomenon has been studied by us and others, especially during the second postnatal week in rodents when muscle fibers Endonuclease make the transition from double and occasionally triple innervation to their adult state of single innervation (Sanes and Lichtman, 1999 and Tapia and Lichtman, 2013). For technical reasons, it has remained unclear whether much more extensive circuit alterations occur in the first postnatal week or even prenatally. Knowing the extent of the early

developmental reorganization would be helpful in resolving several outstanding questions. For example, in mature muscles, motor neurons tend to innervate muscle fibers of a single type. The origin of this so-called motor unit homogeneity remains incompletely understood, with a number of different factors putatively playing a role including the following: specific targeting of axons to certain muscle fibers and not others, conversion of axons by retrograde signals from the muscle fibers, conversion of muscle fibers by activity or other signals from nerves, and synapse elimination of mismatched nerve-muscle connections. Knowing which axons initially contact each muscle fiber would be helpful in understanding the importance of several of these possibilities. Moreover, study of the developing neuromuscular system can reveal detailed circuit information, such as the number of postsynaptic cells innervated by an axon or the contact areas of all the different axons innervating the same postsynaptic cell, data that would be difficult to obtain in less accessible parts of the nervous system.

In a subset of these patients, the sporadic nature of the disease could potentially be explained by the early death of one or both parents (3/22), adoption (1/22), or a lack of sufficient information (8/22); however, in 10 patients the clinical records suggested a true sporadic nature of the disease. The GGGGCC repeat was found in 18.3% of all patients with FTLD-TDP pathology from the MCF brain bank, and explained 22.5% of familial cases in this series. It should be noted however,

that this is a dementia-focused series with an underrepresentation of ALS. The frequency in our clinical FTD patient series was 3.0% of sporadic cases and 11.7% of familial patients. In our clinical ALS series, 4.1% of the sporadic and 23.5% of patients with a positive family history carried repeat expansions. this website Importantly, a direct comparison of the frequency of repeat expansions in C9ORF72 with mutations in SOD1, TARDBP, and FUS revealed GGGGCC expansions to be the most common genetic

cause of sporadic and familial ALS in our clinical series ( Table 1). In clinical FTD, GGGGCC repeat expansions were found to be more common than either GRN or microtubule associated protein tau (MAPT) mutations in familial cases, and of equal frequency to GRN mutations in sporadic FTD. Clinical data was obtained for the 26 unrelated expanded repeat carriers from the clinical FTD series and the 16 unrelated carriers from the ALS series. The median age of onset was comparable in the two series (FTD: Navitoclax price 56.2 years, range 34–72 years; ALS: 54.5 years, range 41–72 years), with a slightly shorter mean disease duration in the ALS patients (FTD: 5.1 ± 3.1 years, range 1–12 years, n = 18; ALS: 3.6 ± 1.6 years, range

1–6 years, n = 7). The FTD phenotype was predominantly behavioral variant FTD (bvFTD) (25/26). Importantly, seven patients from the FTD series (26.9%) had concomitant ALS and eight patients (30.7%) had relatives affected with ALS. In comparison, the frequency of a family history of ALS in the remainder of our FTD population (those without repeat expansions) aminophylline was only 5/348 (1.4%). In the ALS series, all mutation carriers presented with classical ALS with the exception of one patient diagnosed with progressive muscular atrophy without upper motor neuron signs. Three patients (18.8%) were diagnosed with a combined ALS/FTD phenotype. In the ALS patients with expanded repeats, 11/16 (68.8%) reported relatives with FTD or dementia, compared to only 61/213 (28.6%) of ALS patients without repeat expansions. Finally, autopsy was subsequently performed on 11 FTD and three ALS expanded repeat carriers from the clinical series, and in all cases, TDP-43 based pathology was confirmed.